The mental disorder schizophrenia dramatically affects the health and well-being of individuals suffering from it. Individuals with schizophrenia can suffer from a myriad of symptoms and may require significant custodial care and continuous drug and/or behavior therapy, leading to substantial social and economic costs, even in the absence of hospitalization or institutionalization.
The symptoms of schizophrenia are divided into three broad classes: positive symptoms, negative symptoms and cognitive dysfunction.
Positive symptoms generally involve the experience of something in consciousness that should not normally be present. For example, hallucinations and delusions represent perceptions or beliefs that should not normally be experienced. In addition to hallucinations and delusions, patients with schizophrenia frequently have marked disturbances in the logical process of their thoughts. Specifically, psychotic thought processes are characteristically loose, disorganized, illogical, or bizarre. These disturbances in thought process frequently produce observable patterns of behavior that are also disorganized and bizarre. The severe disturbances of thought content and process that comprise the positive symptoms often are the most recognizable and striking features of schizophrenia.
In addition to positive symptoms, patients with schizophrenia have been noted to exhibit major deficits in motivation and spontaneity. These symptoms are referred to as negative symptoms.
While positive symptoms represent the presence of something not normally experienced, negative symptoms reflect the absence of thoughts and behaviors that would otherwise be expected and thus reflect a decrease or loss of normal function or the loss or absence of normal behaviors. Negative symptoms of schizophrenia include, for example, flat or blunted affect, lack of concrete thoughts, anhedonia, poor motivation, loss of spontaneity, and loss of initiative. Inflexibility or rigidity of thought represents impairment in the ability to think abstractly. Blunting of affect refers to a general reduction in the ability to express emotion. Motivational failure and inability to initiate activities represent an important source of long-term disability in schizophrenia. Anhedonia reflects a deficit in the ability to experience pleasure and to react appropriately to pleasurable situations.
Positive symptoms such as hallucinations are responsible for much of the acute distress associated with schizophrenia. Negative symptoms appear to be responsible for much of the chronic and long-term disability associated with the disorder. Current treatments for schizophrenia have shown limited benefit in the treatment of negative symptoms.
Negative symptoms of schizophrenia can be further subdivided into primary and secondary negative symptoms. Primary negative symptoms exclude symptoms that are better accounted for by medication side-effects, post-psychotic depression or demoralization. Rather, examples of primary negative symptoms include: affective flattening (for example emotional immobility, unresponsiveness, poor eye contact, and limited body movement); alogia (where the patient exhibits poverty of speech and usually manifests itself by the patient making brief replies during conversation), avolition (the inability to initiate and persist in goal-directed activities), anhedonia, dysphoric mood (depression, anxiety and anger), disturbances in sleep pattern (sleeping during the day, restlessness/night-time activity), abnormal psychomotor activity (pacing, rocking, apathetic immobility), and lack of insight.
Secondary negative symptoms, some of which occur in association with positive symptoms and/or medication side-effects, include for example, movement disorders such as extrapyramidal symptoms, akathisia, tardive dyskinesia and demoralization.
In addition to positive and negative symptoms, patients with schizophrenia also suffer from general symptoms. General symptoms of schizophrenia include, but are not limited to, somatic concern (e.g., physical complaints or beliefs about bodily illness or malfunctions), anxiety, feelings of guilt, tension (e.g., overt physical manifestations of fear, anxiety, and agitation, such as stiffness, tremor, profuse sweating, and restlessness), mannerisms and posturing (e.g., unnatural movements or posture as characterized by an awkward, stilted, disorganized, or bizarre appearance), depression, motor retardation (e.g., reduction in motor activity as reflected in slowing or lessening of movements and speech, diminished responsiveness to stimuli, and reduced body tone), uncooperativeness, unusual thought content (ranging from those which are remote or atypical to those which are distorted, illogical, and patently absurd), disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, and active social avoidance. Other general symptoms and examples thereof can be found.
There remains a need to identify medicaments and methods for use in the treatment of negative symptoms of schizophrenia, and furthermore, compositions and methods of treatment which improve on the efficacy of existing therapies.
The sigma receptor/binding sites of the brain are important targets for the development of antipsychotic drugs that are free from the side effects of traditional antipsychotic drugs, or have reduced side effects compared to traditional antipsychotic drugs which have antagonistic activity on the dopamine D2 receptor.
The sigma 1 receptor binding site has been characterized as having high affinity for haloperidol, di-o-tolylguanidine (DTG) and (+)-benzomorphanes such as (+)-pentazocine. The sigma 2 receptor binding site has been characterized as having high affinity for haloperidol and DTG, but low affinity for (+)-benzomorphane.
The sigma 2 receptor binding site in brain exists in the hypothalamus, cerebellum, pons medulla and medulla oblongata. In the hippocampus, frontal lobe and occipital lobe of rat brains, it exists more abundantly than the sigma 1 binding site. It is believed that the sigma 2 binding site is involved in motility functions, especially dystonia.
U.S. Pat. No. 7,166,617, incorporated herein by reference in its entirety, discloses cyclic amide ketone derivatives having high affinity for the sigma receptor, along with some affinity at the 5-HT2A receptor, but without any dopamine receptor binding properties. Certain compounds disclosed in that patent also have high affinity for the sigma ligand binding site and low inhibition constant Ki for sigma 1 and/or sigma 2 (high potency), as well as selective binding profiles completely different from those of conventional known compounds. Such compounds may be useful for treatment of diseases that can be therapeutically and/or preventively treated by the nerve control function of the sigma ligands. Such diseases include, for example, diseases of the central nervous system, gastrointestinal tract, and cardiovascular system. There are potential applications to neurodegenerative disorders, pain, drug addiction and cancer. However, the properties and characteristics of specific derivatives were not disclosed in U.S. Pat. No. 7,166,617 (“the '617 patent”).
PCT application PCT/US2011/044697 (WO 2012/012524), incorporated herein by reference in its entirety, discloses methods of treating schizophrenia utilizing the ketone derivatives of the '617 patent. The derivatives are shown to be useful to treat one or more negative symptoms of schizophrenia. The application therefore provides methods and compositions for treating various aspects of schizophrenia. In particular, the application discloses the results of human trials in schizophrenics that demonstrate immediate and sustained improvements in negative symptoms and cognitive functions, and some improvement in positive symptoms. Improvements in mood, anxiety and sleep were particularly noted.